WO2002000249A2 - Multivalent vaccine composition - Google Patents

Multivalent vaccine composition Download PDF

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Publication number
WO2002000249A2
WO2002000249A2 PCT/EP2001/007288 EP0107288W WO0200249A2 WO 2002000249 A2 WO2002000249 A2 WO 2002000249A2 EP 0107288 W EP0107288 W EP 0107288W WO 0200249 A2 WO0200249 A2 WO 0200249A2
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WO
WIPO (PCT)
Prior art keywords
capsular polysaccharide
immunogenic composition
pneumoniae serotype
infiuenzae
meningitidis
Prior art date
Application number
PCT/EP2001/007288
Other languages
English (en)
French (fr)
Other versions
WO2002000249A3 (en
Inventor
Dominique Boutriau
Carine Capiau
Pierre Michel Desmons
Dominique Lemoine
Jan Poolman
Original Assignee
Glaxosmithkline Biologicals S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Priority claimed from GBGB0015999.6A external-priority patent/GB0015999D0/en
Priority claimed from GB0108363A external-priority patent/GB0108363D0/en
Priority claimed from GBGB0108364.1A external-priority patent/GB0108364D0/en
Priority to IL15350601A priority Critical patent/IL153506A0/xx
Priority to MXPA03000198A priority patent/MXPA03000198A/es
Priority to HU0301413A priority patent/HU228384B1/hu
Priority to HU1000593A priority patent/HU227893B1/hu
Priority to SK1843-2002A priority patent/SK288007B6/sk
Priority to APAP/P/2002/002700A priority patent/AP1695A/en
Priority to KR1020027017928A priority patent/KR100837917B1/ko
Priority to BRPI0112057A priority patent/BRPI0112057B8/pt
Priority to EA200201240A priority patent/EA006313B1/ru
Priority to CN018146198A priority patent/CN1449293B/zh
Priority to UA20021210397A priority patent/UA76952C2/uk
Priority to NZ523319A priority patent/NZ523319A/en
Priority to DK01960390.1T priority patent/DK1296715T4/en
Priority to PL360265A priority patent/PL210015B1/pl
Application filed by Glaxosmithkline Biologicals S.A. filed Critical Glaxosmithkline Biologicals S.A.
Priority to EP01960390.1A priority patent/EP1296715B2/en
Priority to AU8189501A priority patent/AU8189501A/xx
Priority to AT01960390T priority patent/ATE534402T1/de
Priority to ES01960390.1T priority patent/ES2375704T5/es
Priority to DZ013399A priority patent/DZ3399A1/xx
Priority to JP2002505030A priority patent/JP4870895B2/ja
Priority to CA2412497A priority patent/CA2412497C/en
Priority to AU2001281895A priority patent/AU2001281895C1/en
Priority to HU1000594A priority patent/HU227613B1/hu
Priority to BR122012003821A priority patent/BR122012003821B8/pt
Priority to SI200131007T priority patent/SI1296715T2/sl
Publication of WO2002000249A2 publication Critical patent/WO2002000249A2/en
Publication of WO2002000249A3 publication Critical patent/WO2002000249A3/en
Priority to IL153506A priority patent/IL153506A/en
Priority to NO20026175A priority patent/NO332495B1/no
Priority to BG107422A priority patent/BG66238B1/bg
Priority to HK03106153.7A priority patent/HK1055244A1/xx
Priority to BG10110518A priority patent/BG66249B1/bg
Priority to US13/439,829 priority patent/US9233151B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0016—Combination vaccines based on diphtheria-tetanus-pertussis
    • A61K39/0018—Combination vaccines based on acellular diphtheria-tetanus-pertussis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/385—Haptens or antigens, bound to carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • A61K39/092—Streptococcus
    • A—HUMAN NECESSITIES
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    • A61K39/095—Neisseria
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    • A61K39/102—Pasteurellales, e.g. Actinobacillus, Pasteurella; Haemophilus
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    • A61K39/12—Viral antigens
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    • A—HUMAN NECESSITIES
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    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5252—Virus inactivated (killed)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55583—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/70—Multivalent vaccine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32611—Poliovirus
    • C12N2770/32634—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to new combination vaccine formulations.
  • Combination vaccines which provide protection against multiple pathogens
  • the well-documented phenomenon of antigenic competition (or interference) complicates the development of multi-component vaccines.
  • Antigenic interference refers to the observation that administering multiple antigens often results in a diminished response to certain antigens relative to the immune response observed when such antigens are administered individually.
  • Combination vaccines are known which can prevent Bordetella pertussis, Clostridium tetani, Corynebacterium diphtheriae, and optionally Hepatitis B virus and/or Haemophilus infiuenzae type b (see, for instance, WO 93/24148 and WO 97/00697).
  • the present invention concerns the manufacture of the most ambitious multi- valent vaccines to date, the administration of which can prevent or treat infection by Bordetella pertussis, Clostridium tetani, Corynebacterium diphtheriae, Hepatitis B virus, Haemophilus infiuenzae and N. meningitidis, and preferably also Hepatitis A virus and/or Polio virus, wherein the components of the vaccine do not significantly interfere with the irnmunological performance of any one component of the vaccine.
  • the present invention provides a multi-valent immunogenic composition for conferring protection in a host against disease caused by Bordetella pertussis, Clostridium tetani, Corynebacterium diphtheriae, Hepatitis B virus, Haemophilus infiuenzae and N. meningitidis comprising:
  • TT tetanus toxoid
  • TT is preferably produced by purification of the toxin from a culture of Clostridium tetani followed by chemical detoxification, but is alternatively made by purification of a recombinant, or genetically detoxified analogue of the toxin (for example, as described in EP 209281).
  • 'Tetanus toxoid' also encompasses immunogenic fragments of the full-length protein (for instance Fragment C - see EP 478602).
  • DT diphtheria toxoid
  • DT is preferably produced by purification of the toxin from a culture of Corynebacterium diphtheriae followed by chemical detoxification, but is alternatively made by purification of a recombinant, or genetically detoxified analogue of the toxin (for example, CRM197, or other mutants as described in US 4,709,017, US 5,843,711, US 5,601,827, and US 5,917,017).
  • Acellular pertussis components are well known in the art. Examples include pertussis toxoid (PT), filamentous haemagluttinin (FHA), pertactin (PRN) and agglutinogens 2 and 3. These antigens are partially or highly purified. Preferably 2 or more acellular pertussis components are used in the vaccine. More preferably 2, 3, 4 or all 5 of the above example acellular pertussis components are incorporated in the vaccine. Most preferably PT, FHA and PRN are included. PT may be produced by a variety of manners, for instance by purification of the toxin from a culture of B. pertussis followed by chemical detoxification, or alternatively by purification of a genetically detoxified analogue of PT (for example, as described in US 5,085,862).
  • the bacterial capsular polysaccharide conjugates may comprise any carrier peptide, polypeptide or protein comprising at least one T-helper epitope.
  • the carrier protein(s) used is selected from the group comprising: tetanus toxoid, diphtheria toxoid, CRM197, recombinant diphtheria toxin (as described in any of US 4,709,017, WO 93/25210, WO 95/33481, or WO 00/48638), pneumolysin (preferably chemically detoxified, or a detoxified mutant) from S. pneumoniae, OMPC from N. meningitidis, and protein D (PD) from H. infiuenzae (EP 594610).
  • polysaccharide antigens contained therein are conjugated to more than one carrier.
  • (n-1) of the polysaccharides could be carried (separately) on one type of carrier, and 1 on a different carrier, or (n-2) on one, and 2 on two different carriers, etc.
  • n-1 of the polysaccharides could be carried (separately) on one type of carrier, and 1 on a different carrier, or (n-2) on one, and 2 on two different carriers, etc.
  • Protein D is advantageously used as a carrier in the compositions of the invention as it may be used for various (2, 3, 4 or more) polysaccharides in a composition without a marked carrier suppression effect.
  • Hib is present as a TT conjugate
  • MenA, MenC, MenY and MenW are either TT or PD conjugates.
  • Protein D is also a useful carrier as it provides a further antigen which can provide protection against H infiuenzae.
  • the polysaccharide may be linked to the carrier protein by any known method
  • CDAP conjugation is carried out (WO 95/08348).
  • the cyanylating reagent 1-cyano-dimethylaminopyridinium tetrafluoroborate (CDAP) is preferably used for the synthesis of polysaccharide- protein conjugates.
  • the cyanilation reaction can be performed under relatively mild conditions, which avoids hydrolysis of the alkaline sensitive polysaccharides. This synthesis allows direct coupling to a carrier protein.
  • the above immunogenic composition may further comprise one, two, three, four, five, six or seven components selected from the following list: N. meningitidis type Y polysaccharide [MenY] (preferably conjugated), N. meningitidis type W polysaccharide [MenW] (preferably conjugated), the Vi polysaccharide of Salmonella typhi, N. meningitidis (preferably serotype B) outer membrane vesicles, one or more N.
  • N. meningitidis type Y polysaccharide [MenY] preferably conjugated
  • N. meningitidis type W polysaccharide [MenW] preferably conjugated
  • the Vi polysaccharide of Salmonella typhi preferably serotype B
  • N. meningitidis preferably serotype B
  • the immunogenic compositions of the invention are preferably formulated as a vaccine for in vivo administration to the host in such a way that the individual components of the composition are formulated such that the immunogenicity of individual components is not substantially impaired by other individual components of the composition.
  • an antibody titre against each component is obtained which is more than 60%, preferably more than 70%, more preferably more than 80 %, still more preferably more than 90%, and most preferably more than 95-100% of the titre obtained when the antigen is administered in isolation.
  • the immunogenic compositions of the invention are preferably formulated as a vaccine for in vivo administration to the host, such that they confer an antibody titre superior to the criterion for seroprotection for each antigenic component for an acceptable percentage of human subjects. This is an important test in the assessment of a vaccine's efficacy throughout the population.
  • Antigens with an associated antibody titre above which a host is considered to be seroconverted against the antigen are well known, and such titres are published by organisations such as WHO.
  • the immunogenic composition of the invention are preferably adjuvanted.
  • Suitable adjuvants include an aluminium salt such as aluminium hydroxide gel (alum) or aluminium phosphate, but may also be a salt of calcium, iron or zinc, or may be an insoluble suspension of acylated tyrosine, or acylated sugars, cationically or anionically derivatised polysaccharides, or polyphosphazenes.
  • the adjuvant may also be selected to be a preferential inducer of a TH1 type of response to aid the cell mediated branch of the immune response.
  • Thl-type cytokines tend to favour the induction of cell mediated immune responses to a given antigen, whilst high levels of Th2-type cytokines tend to favour the induction of humoral immune responses to the antigen.
  • Suitable adjuvant systems which promote a predominantly Thl response include, Monophosphoryl lipid A or a derivative thereof, particularly 3-de-O-acylated monophosphoryl lipid A, and a combination of monophosphoryl lipid A, preferably 3- de-O-acylated monophosphoryl lipid A (3D-MPL) together with an aluminium salt.
  • An enhanced system involves the combination of a monophosphoryl lipid A and a saponin derivative, particularly the combination of QS21 and 3D-MPL as disclosed in WO 94/00153, or a less reactogenic composition where the QS21 is quenched with cholesterol as disclosed in WO 96/33739.
  • a particularly potent adjuvant formulation involving QS21, 3D-MPL and tocopherol in an oil in water emulsion is described in WO 95/17210.
  • the vaccine may additionally comprise a saponin, more preferably QS21.
  • the formulation may also comprises an oil in water emulsion and tocopherol (WO 95/17210).
  • Unmethylated CpG containing oligonucleotides are also preferential inducers of a TH1 response and are suitable for use in the present invention.
  • Aluminium salts are preferred adjuvants in the above immunogenic compositions.
  • HepB should preferably be adsorbed onto aluminium phosphate before admixing with the other components.
  • the polysaccharide conjugates may be unadjuvanted.
  • the present invention also provides a method for producing a vaccine formulation comprising the step of mixing the components of the vaccine together with a pharmaceutically acceptable excipient.
  • a particularly preferred DTPw composition of the invention comprises: TT, DT, Pw, HepB (preferably adsorbed onto aluminium phosphate), Hib (preferably conjugated onto TT and/or unadsorbed), MenA (preferably conjugated onto protein D), and MenC (preferably conjugated onto protein D).
  • the vaccine may be supplied in 2 containers, the first containing DTPw-HepB in a liquid form, and a second containing Hib-MenA-MenC in a lyophilised form. The contents of the containers may be mixed extemporaneously before administering to a host in a single injection.
  • an immunogenic composition or vaccine as herein described for use in a medicament.
  • a method of immunising a human host against disease caused by Bordetella pertussis, Clostridium tetani, Corynebacterium diphtheriae, Hepatitis B virus, Haemophilus infiuenzae and N. meningitidis which method comprises administering to the host an immunoprotective dose of the immunogenic composition of the invention is also provided.
  • the vaccine preparations of the present invention may be used to protect or treat a mammal susceptible to infection, by means of administering said vaccine via systemic or mucosal route.
  • These administrations may include injection via the intramuscular, intraperitoneal, intradermal or subcutaneous routes; or via mucosal administration to the oral/alimentary, respiratory, genitourinary tracts.
  • each vaccine dose is selected as an amount which induces an immunoprotective response without significant, adverse side effects in typical vaccines. Such amount will vary depending upon which specific immunogen is employed and how it is presented. Generally, it is expected that each dose will comprise 0.1-100 ⁇ g of polysaccharide, preferably 0.1-50 ⁇ g, preferably 0.1-10 ⁇ g, of which 1 to 5 ⁇ g is the most preferable range.
  • the content of protein antigens in the vaccine will typically be in the range 1- lOO ⁇ g, preferably 5-50 ⁇ g, most typically in the range 5 - 25 ⁇ g.
  • subjects may receive one or several booster immunisations adequately spaced.
  • Vaccine preparation is generally described in Vaccine Design ("The subunit and adjuvant approach” (eds Powell M.F. & Newman M.J.) (1995) Plenum Press New York). Encapsulation within liposomes is described by Fullerton, US Patent 4,235,877.
  • Hib a substantially lower dose of Hib can be used in the combination vaccine (compared with the standard dose of 10 ⁇ g per 0.5 mL dose) to obtain at least equivalent antibody titres against the H infiuenzae type b capsular polysaccharide antigen. This is contrary to what would have been expected.
  • a multi-valent immunogenic composition comprising killed whole-cell Bordetella pertussis (Pw), tetanus toxoid (TT), diphtheria toxoid (DT), and a conjugate of a carrier protein and the capsular polysaccharide of H. infiuenzae type B (Hib - preferably conjugated to TT, DT or CRM197), wherein the amount of conjugate per 0.5 mL dose of bulk vaccine is 1-8 ⁇ g, and the immunogenicity of the conjugate is equivalent or improved over such compositions comprising larger amounts of conjugate.
  • Hepatitis B surface antigen may also be included.
  • the amount of conjugate per 0.5 mL dose of bulk vaccine is less than 10 ⁇ g (of polysaccharide in the conjugate), more preferably 1-7 or 2-6 ⁇ g, and most preferably about 2.5, 3, 4 or 5 ⁇ g.
  • the Hib conjugate is not adsorbed onto aluminium adjuvant salt before being mixed with the DTPw vaccine.
  • combination vaccines comprising a Hib conjugate elicits significantly higher anti-Hib antibody titres in a host (compared with a monovalent, unadsorbed Hib conjugate vaccine) if the Hib conjugate is administered in a vaccine additionally comprising 1, but particularly 2 or more additional bacterial polysaccharides and the Hib polysaccharide (and preferably all the polysaccharides) of the vaccine are not adsorbed onto an adjuvant (particularly aluminium salts).
  • a further, independent, aspect of the invention therefore is the provision of a multi-valent immunogenic composition
  • a multi-valent immunogenic composition comprising a conjugate of a carrier protein and the capsular polysaccharide of H infiuenzae type B (Hib), wherein said composition additionally comprises 1, but particularly 2 or more further bacterial polysaccharides (preferably more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) capable of conferring protection to a host against infection by the bacteria from which they are derived, and wherein the Hib polysaccharide (and preferably none of said polysaccharides) in the composition are adsorbed onto an aluminium adjuvant salt. Most preferably there is no aluminium adjuvant salt present in the composition.
  • an antigen not being 'adsorbed onto an aluminium adjuvant salt' it is meant that an express or dedicated adsorption step for the antigen on fresh aluminium adjuvant salt is not involved in the process of formulating the composition.
  • Hib may be conjugated to any carrier which can provide at least one T-helper epitope (examples of which are described above), and preferably tetanus toxoid.
  • the further bacterial polysaccharides are also conjugated to a carrier protein (examples of which are described above).
  • the capsular polysaccharide of H. infiuenzae type B and the further polysaccharides are not conjugated to the same carrier (Hib and none of the further polysaccharides share the same carrier), particularly where the carrier is CRM197.
  • at least one of the polysaccharides of the composition is conjugated onto protein D, however this is not essential for the performance of the invention - indeed neither the Hib nor any of the further polysaccharides need be conjugated onto protein D.
  • Hib and further bacterial polysaccharides (and conjugates thereof) are the only antigens present in the composition.
  • an amount of polysaccharide which capable of conferring protection to a host can be readily determined by the skilled person. Generally, it is expected that each dose will comprise 0.1-100 ⁇ g of polysaccharide, preferably 0.1-50 ⁇ g, preferably 0.1-10 ⁇ g, of which 1 to 5 ⁇ g is the most preferable range.
  • the Hib conjugate is preferably present in an amount of 3-15 ⁇ g (of polysaccharide in the conjugate), more preferably 4-12 ⁇ g and most preferably 5-10 ⁇ g.
  • the further bacterial polysaccharides are selected from a group consisting of: N. meningitidis serogroup A capsular polysaccharide (MenA), N. meningitidis serogroup C capsular polysaccharide (MenC), N. meningitidis serogroup Y capsular polysaccharide (MenY), N.
  • meningitidis serogroup W capsular polysaccharide (MenW), Group B Streptococcus group I capsular polysaccharide, Group B Streptococcus group II capsular polysaccharide, Group B Streptococcus group III capsular polysaccharide, Group B Streptococcus group IV capsular polysaccharide, Group B Streptococcus group V capsular polysaccharide, Staphylococcus aureus type 5 capsular polysaccharide, Staphylococcus aureus type 8 capsular polysaccharide, Vi polysaccharide from Salmonella typhi, N. meningitidis LPS, M.
  • LPS catarrhalis LPS
  • H infiuenzae LPS H infiuenzae LPS.
  • LPS it is meant either native lipo-polysaccharide (or lipo-oligosaccharide), or lipo-polysaccharide where the lipid A portion has been detoxified by any of a number of known methods (see for example WO 97/18837 or WO 98/33923), or any molecule comprising the O-polysaccharide derived from said LPS.
  • N. meningitidis LPS it is meant one or more of the 12 known immunotypes (LI, L2, L3, L4, L5, L6, L7, L8, L9, L10, LI 1 or L12).
  • the amount of PS in each of the above conjugates may be 5 or 10 ⁇ g each per 0.5 mL human dose.
  • the above compositions may also include N. meningitidis serotype B outer membrane vesicles, or one or more N. meningitidis serotype B outer membrane (surface-exposed) proteins, or one or more N. meningitidis LPS (as defined above) to make a global meningitis vaccine.
  • MenA, MenC and MenY are either TT or PD conjugates.
  • the further bacterial polysaccharides may also be selected from any of the capsular pneumococcal polysaccharides (preferably more than 7, more preferably 11 or more, and most preferably 13 or more) such as from serotype: 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F or 33F.
  • the pneumococcal polysaccharides are conjugated (most preferably PD conjugates).
  • pneumococcal polysaccharides derived from at least four serotypes may be selected from the above list. More preferably polysaccharides from more than 7 serotypes are included in the composition, for instance at least 11 serotypes.
  • the composition in one embodiment includes 11 capsular polysaccharides derived from serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (preferably conjugated).
  • polysaccharide antigens preferably conjugated
  • further polysaccharide antigens for example 23 valent (such as serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11 A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F), are also contemplated by the invention.
  • serotypes 8 and 12F are advantageously included to form a 13/15 valent vaccine.
  • serotypes 6A and 19A are advantageously included to form a 13 valent vaccine.
  • the pneumococcal polysaccharides may or may not be adsorbed onto aluminium adjuvant salts.
  • Hib preferably lyophilised
  • the pneumococcal polysaccharides preferably in a liquid form
  • no (significantly) detrimental effect occurs to the pneumococcal polysaccharide conjugates (in terms of protective efficacy) in the combination as compared to their administration in isolation.
  • GMC post-primary geometric mean concentrations
  • Another indication that no detrimental effect has occurred is if the % of subjects with antibody concentrations of no less than 0.5 ⁇ g/ml differs by no more than 10%) (preferably less than 9, 7, 5, 3 or 1%) when comparing 1 month post-primary administrations of the vaccine of the invention versus the vaccine without Hib conjugate.
  • Hib and further bacterial 'polysaccharides' the preferred embodiment
  • the invention may be extended to Hib and further bacterial 'oligosaccharides' (which naturally have a low number of repeat units, or which are polysaccharides reduced in size for manageability, but are still capable of inducing a protective immune response in a host) which are well known in the vaccine art.
  • the multi-valent immunogenic composition of this aspect of the invention is formulated as a vaccine for in vivo administration to the host wherein the individual components of the composition are formulated such that the immunogenicity of individual components is not impaired by other individual components of the composition (see above definition).
  • no (significantly) detrimental effect occurs to the further bacterial polysaccharides (in terms of protective efficacy) in the combination as compared to their administration in isolation.
  • the multi-valent immunogenic composition of this aspect of the invention is formulated as a vaccine for in vivo administration to the host, which confers an antibody titre superior to the criterion for seroprotection for each antigenic component for an acceptable percentage of human subjects (see above definition).
  • compositions of this aspect of the invention are preferably formulated in a vaccine.
  • the use of the of the multi-valent immunogenic composition of this aspect of the invention in the manufacture of a medicament for the treatment or prevention of diseases caused by infection by Haemophilus infiuenzae (and preferably also those organisms from which the further bacterial polysaccharides are derived) is also envisioned, as is a method of immunising a human host against disease caused by Haemophilus infiuenzae (and preferably also those organisms from which the further bacterial polysaccharides are derived), which method comprises administering to the host an immunoprotective dose of the multi-valent immunogenic composition of this aspect of the invention.
  • a process for making the multi-valent immunogenic composition of this aspect of the invention comprising the step of mixing together the individual components. If the further bacterial polysaccharides are to be adsorbed onto an aluminium adjuvant salt, this should be done before Hib is added to the formulation. Preferably an excess of aluminium adjuvant salt should not be- used. Most preferably the Hib should be added to the aluminium adjuvanted further polysaccharide extemporanoeusly to the composition being administered to a host. All cited references and publications are incorporated by reference herein.
  • Example 1 Preparation of a DT-TT-Pw-HepB (DTPw-HepB) Vaccine
  • the vaccine is commercially available under the name Tritanrix-HepBTM (SmithKline Beecham Biologicals).
  • MenAC-Hib N. meningitidis type A capsular polysaccharide conjugated onto protein D (using the CDAP technique), N. meningitidis type C capsular polysaccharide conjugated onto protein D and H. infiuenzae type b capsular polysaccharide conjugated onto TT were mixed together in an amount of 5 ⁇ g of each polysaccharide in each conjugate per 0.5 mL human dose. The pH was adjusted to 6.1, and was lyophilised in the presence of sucrose.
  • MenC-Hib N. meningitidis type C capsular polysaccharide conjugated onto protein D (using the CDAP technique) and H. infiuenzae type b capsular polysaccharide conjugated onto TT were mixed together in an amount of 5 ⁇ g of polysaccharide in each conjugate per 0.5 mL human dose. The pH was adjusted to
  • N. meningitidis type C capsular polysaccharide conjugated onto protein D and H. infiuenzae type b capsular polysaccharide conjugated onto TT were each adsorbed separately in saline onto aluminium phosphate (5 ⁇ g of each conjugate onto 100 ⁇ g, 100 ⁇ g and 60 ⁇ g Al , respectively, per dose).
  • the adsorbed vaccines were mixed together at a pH of 6.1 and were lyophilised in the presence of sucrose.
  • MenAC-Hib 001 evaluates the immunogenicity, reactogenicity and safety induced by MenC-Hib and MenAC-Hib (adsorbed and unadsorbed) made by the above example given as a three-dose primary vaccination in infants.
  • the formulations that were evaluated were a lyophilized plain and adsorbed formulation of Men AC-Hib and a plain formulation of MenC-Hib. These three formulations were administered to the three first study groups of infants at 3, 4 and 5 months of age; Tritanrix-HepBTM was given concomitantly (as a separate injection) to these three groups.
  • the plain formulation of Men AC-Hib was also reconstituted within a liquid diphtheria, tetanus, whole-cell pertussis, hepatitis B combined vaccine (Tritanrix-HepBTM) and administered as a single injection to the fourth study group of infants at 3, 4 and 5 months of age.
  • the fifth group (control) was administered Tritanrix-HepBTM-Hib vaccine at 3, 4, 5 months of age.
  • the study groups were:
  • each formulation that was evaluated induced a good immune response against each antigen (antibodies against meningococcal groups A and C, Poly-Ribosyl-Phosphate (the capsular polysaccharide of H infiuenzae type b), Diphtheria toxoid, Tetanus toxoid, Bordetella pertussis and hepatitis B were measured).
  • Each vaccine formulation was well tolerated.
  • This test is an ELISA test that measures IgG content against meningococcal polysaccharide A.
  • Fig. 3 shows the RCC graphs of the data. There is no interference of the MenA polysaccharide antigen to induce at least the same quantity of antibodies when present in a DTPw-HepB /MenAC-Hib vaccine.
  • This test is a bactericidal test that measures the bactericidal antibodies against meningococcus serogroup A. There is no interference of the MenA polysaccharide antigen to induce at least the same quantity of antibodies when present in a DTPw- HepB /MenAC-Hib vaccine.
  • Post III anti PSC meningococcus C capsular polysaccharide
  • This test is an ELISA test that measures IgG content against meningococcal polysaccharide C.
  • Fig 4 shows a RCC graph of the data.
  • SBA-MenC is a bactericidal test that measures the bactericidal activity of the serum against meningococcus C. It is a measure of functional antibodies.
  • Fig 5 shows a RCC graph of the data. There is no interference on the MenC polysaccharide antigen to induce the same quantity of functional antibodies when it is present in a DTPw-HepB/MenAC-Hib vaccine.
  • This test is a bactericidal test that measures the bactericidal antibodies against meningococcus serogroup A. It is a measure of functional antibodies. There is no interference on the MenC polysaccharide antigen to induce the same quantity of functional antibodies when it is present in a DTPw-HepB/MenAC-Hib vaccine.
  • BP refers to B. pertussis.
  • An ELISA test was done measuring IgG against the whole cell bacteria.
  • GMT Geometric Mean Titre
  • Example 4 Preparation of a Hib - 11 valent pneumococcal conjugate (Hib/StrepllV) Vaccine
  • the pneumococcal vaccine had previously been adsorbed onto 0.5 mg Al 3+ (as AlPO 4 ).
  • Example 5 Clinical Trials on the Vaccine of Example 4
  • Example 4 The vaccine of Example 4 and a control vaccine were administered in a three- dose (3, 4, 5 months of age) schedule to German infants.
  • the immune response results (measured 1 month after the last primary administration) were as follows.
  • Group A 1 lPn-PD + Infanrix-HeXa ,TM (Infanrix-Penta plus added Hib conjugate)
  • Group D 1 lPn-PD/Hib + Infanrix-PeNTa
  • ody concentrations no less than 1.0 ⁇ g/ml.
  • Hiberix (unadsorbed Hib-TT conjugate) has a GMC after a similar administration schedule of about 6 ⁇ g/ml.
  • the immune response, in terms of ELISA antibodies, of infants who received the l lPn-PD/Hib vaccine was similar to that observed for those who received the 1 lPn-PD vaccine for all of the serotypes, with the exception of serotypes 1, 3 and 9V for which a trend to lower geometric mean concentrations was observed for the 1 lPn- PD/Hib vaccine. However, these differences were not significant as shown by the overlapping of 95% confidence intervals.
  • the l lPn-PD/Hib vaccine induced functional (opsonophagocytic) antibodies to all 11 serotypes.
  • Example 6 Clinical Trial on the effect of lower amounts of Hib in a DTPwHepB vaccine
  • Group 2 DTPw-Hep
  • GCTs Geometric Mean Titers
  • the low dose formulation surprisingly has the highest GMT values. This effect should be even greater if the Hib-TT vaccine is unadsorbed.

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